Carfilzomib is a selective proteasome inhibitor indicated for the treatment of multiple myeloma. Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib has antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.
Carfilzomib is commercially marketed under the name Kyprolis® in single dose vials containing either 30 mg or 60 mg of the active ingredient. Each vial, in addition to lyophilized carfilzomib, also contains sulfobutylether beta-cyclodextrin, citric acid and sodium hydroxide for pH adjustment (target pH 3.5).
The lyophilized products require reconstitution prior to intravenous infusion. The process of reconstitution requires several lengthy and complex steps comprising aseptically reconstituting each vial by slowly injecting sterile water for injection through the stopper, directing the water onto the inside wall of the vial to minimize foaming. After the water is added, the vial is gently swirled and/or slowly inverted for about 1 minute, or until complete dissolution occurs. If foaming occurs, the solution is allowed to settle in the vial until foaming subsides (approximately 5 minutes) and the solution becomes clear. After reconstitution, the vial must be visually inspected, and a dose that appears to have any discoloration or particulate matter must be discarded.
One of the difficulties with the commercially available formulation is that the administration process is complex and involves many steps. As described above, the person administering the drug must first create a solution and then subsequently transfer that premix solution into an infusion bag. As carfilzomib is extremely toxic, strict precautions have to be taken in order to minimize handling hazards involving dilution of injection and subsequent preparation of an infusion solution. In making the premix solution, the medical practitioner is required to manually invert the vial for 1 minute repeatedly to allow for complete dissolution. The prescribing information for KYPROLIS® gives very clear instructions not to shake the vial to avoid foaming or spillage. Foaming may result in potency loss. A further difficulty of the commercialized available product is that the premix solution must be added to the infusion bag soon after making of such an admixture. Further, once added to the infusion bag, the carfilzomib has limited stability. The prescribing information notes that once reconstituted, the carfilzomib solutions are stable for only 24 hours when refrigerated, and only four hours at room temperature.
There have been efforts to obtain improved carfilzomib compositions. For instance, substituted cyclodextrin additives have been explored to enhance the solubility of the active ingredient. However, the high cost and limited accessibility of substituted cyclodextrins limits their use in pharmaceutical compositions
As carfilzomib has extremely low aqueous solubility, the development of a stable carfilzomib injection is very challenging. There remains a need for improved formulations of carfilzomib having improved ease of manufacture, means of administration, and stability over time. There remains a need for formulations which are easy for healthcare providers to prepare and administer. There remains a need for carfilzomib formulations having improved stability over time, especially when stored under ambient conditions.
It is an object of the invention to provide stabilized, ready-to-dilute, carfilzomib formulations.
It is another object of the invention to provide stabilized, ready-to-use, carfilzomib formulations.
It is another object of the invention to provide a process for preparing stabilized, ready-to-dilute, carfilzomib formulations.
It is another object of the invention to provide a process for preparing stabilized, ready-to-use, carfilzomib formulations.
It is another object of the present invention to provide safe, efficacious and easy to use formulations of carfilzomib.
It is another object of the present invention to provide methods for treating patients with multiple myeloma by administering stable ready-to-dilute/ready-to-use parenteral formulations of carfilzomib.